title: Antibody conjugates of 7-ethyl-10-hydroxycamptothecin (SN-38) for targeted cancer chemotherapy.
abstract: CPT-11 is a clinically used cancer drug, and it is a prodrug of the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin). To bypass the need for the in vivo conversion of CPT-11 and increase the therapeutic index, bifunctional derivatives of SN-38 were prepared for use in antibody-based targeted therapy of cancer. The general synthetic scheme incorporated an acetylene-azide click cycloaddition step in the design, a short polyethylene glycol spacer for aqueous solubility, and a maleimide group for conjugation. Conjugates of a humanized anti-CEACAM5 monoclonal antibody, hMN-14, prepared using these SN-38 derivatives were evaluated in vitro for stability in buffer and human serum and for antigen-binding and cytotoxicity in a human colon adenocarcinoma cell line. Conjugates of hMN-14 and SN-38 derivatives 16 and 17 were found promising for further development.
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey 07950, USA.
authors.forename: Sung-Ju
authors.initials: SJ
authors.lastname: Moon
authors.forename: Serengulam V
authors.initials: SV
authors.lastname: Govindan
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.forename: Christopher A
authors.initials: CA
authors.lastname: D'Souza
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Hansen
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000114:Acetylene / Q000737:chemistry; D000906:Antibodies / Q000737:chemistry* / Q000276:immunology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D007700:Kinetics; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D001386:Azides; D000077146:Irinotecan; D000114:Acetylene; D002166:Camptothecin